N-methyl-D-aspartate (NMDA) receptor antagonists such as dextromethorphan are particularly useful for blocking NMDA receptors in the central nervous system (CNS), e.g. to suppress coughing. Besides central nervous activity of NMDA receptor antagonists, their activity in peripheral tissue has attracted attention in clinical research over the last years.
WO 2013/029762 discloses that dextromethorphan and other morphinan-derivatives target NMDA receptors on pancreatic islets for use in the treatment of insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, obesity, and/or diabetic nephropathy (see Marquard et al., Nat. Med. 2015; 21:363-372; see also Ashcroft et al., Cell 2012; 148: 1160-1171). Dextromethorphan has also been successfully used in the treatment of neuropathic pain, such a diabetic neuropathy (see Zhou et al., Expert Rev Clin Pharmacol 2011; 4: 379-388; Shaibani et al., Pain Med 2012; 13: 243-254). Further, recent preclinical studies revealed that NMDA receptor antagonists may inhibit metastasis and tumor growth and an elevated coexpression of NMDA receptors and glutamate exporters in cancer cells correlates with a poor prognosis for cancer patients (see Li et al., Cell 2013; 153: 86-100).
For inhibiting NMDA receptors in peripheral tissues, such as pancreatic islets or cancer cells, it would be desirable to suppress the central activity of NMDA receptor antagonists in order to reduce the frequency and intensity of central nervous adverse effects as observed upon administration of elevated doses of NMDA receptor antagonists, such as dextromethorphan (Marquard et al., Nat. Med. 2015; 21:363-372). The occurrence of central nervous adverse effects, the risk of a so far incalculable long-term neurotoxicity, as well as a potential development of dependency, which may occur in treatment with conventional NMDA receptor antagonists, make it problematic to use NMDA receptor antagonists at higher concentrations over an extended treatment period (see Logan et al., J Anal Toxicol 2009; 33: 99-103; Olney et al., Science 1989; 244: 1360-2; Zhou et al., Expert Rev Clin Pharmacol 2011; 4: 379-388).
WO 2011/014003 discloses a (+)-3-hydroxymorphinan derivative and a pharmaceutical composition comprising the same as an active ingredient, which are useful for preventing or treating a neurodegenerative disease, are provided.
WO 2011/142620 discloses a (+)-3-hydroxymorphinan-based polycycle derivative as a neuroprotective agent for neurodegenerative diseases including Alzheimers's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemic stroke.
WO 2013/029762 relates to a morphinan-derivative that targets NMDA receptors on pancreatic islets. For use in the treatment of a disease or condition, where the disease or condition is insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, obesity, and/or diabetic nephropathy.
JP S60 89474 discloses a morphinan-derivative for use as an antitumor agent.
R. Grewe et al., “Die Totalsynthese des Tetrahydro-desoxycodeins”, Annalen der Chemie, vol. 564, p. 161-198; relates to the synthesis of tetrahydrodesoxycodein.
G. Boccardi et al., “Photochemical Iron(III)-Mediated Autoxidation of Dextromethorphan”, Chem. Pharm. Bull., Pharm. Soc. Japan, vo. 37, no. 2, 1. January 1989, p. 308-310; discloses that the photochemical reaction of dextromethorphan 1 in hydrochloric acid and in the presence of iron(III) salts leads to the 10β-hydroxyderivatives as a major product in addition to the 10-ketoderivative.
Peng et al., “In-vitro investigation of oxazol and urea analogues of morphinan and opioid receptors”, Bioorganic and Medicinal Chem., Pergamon, GB, vol. 15, no. 12, 5 May 2007, p. 4106-4112; discloses a series of 2-amino-oxazole analogs and 2-one-oxazole analogs and their evaluation in-vitro by their binding affinity and μ, δ, and κ opioid receptors.
R. Dixon et al., “Dextromorphan: radioimmunoassay and pharmacokinetics in the dog”, Research Communications in Chem. Pathology and Pharmacology, vol. 22, no. 2, p. 243-255, relates to the development of a specific radioimmunoassay for the determination of the widely used non-narcotic antitussive agent, dextromethorphan in plasma and urine using an antiserum to dextromethorphan which was obtained from rabbits following immunization with an albumin conjugate of (+)-3-methoxymorphinan-17-succinyloxyethyl.
There is a demand for NMDA receptor antagonists that overcome the drawbacks of the prior art. It is therefore an object of the invention to provide NMDA receptor antagonists that have advantages compared to the prior art.
This object has been achieved by the subject-matter of the patent claims.